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Second Gene (second + gene)
Selected AbstractsOptimal designs for estimating penetrance of rare mutations of a disease-susceptibility geneGENETIC EPIDEMIOLOGY, Issue 3 2003Gail Gong Abstract Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers. Genet Epidemiol 24:173,180, 2003. © 2003 Wiley-Liss, Inc. [source] Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1,HUMAN MUTATION, Issue 6 2006P. K. Ilja Boor Abstract Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive cerebral white matter disorder in children. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC is caused by mutations in the gene MLC1, which encodes a novel protein, MLC1. Since the first report, 50 mutations in this gene have been found. Mutations occur throughout the entire coding region and include all different types: 11 splice-site mutations; one nonsense mutation; 24 missense mutations; and 14 deletions and insertions. Until now, six polymorphisms within the coding sequence of MLC1 had been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. Several of the families, in which no mutations are found, also do not show linkage with the MLC1 locus, which suggests a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter, 3, and 5, untranslated regions (UTRs), and intron mutations, which may influence the amino acid composition of the end product. In this work we describe 13 novel mutations, including those found with extended mutation analysis on MLC patients. This study shows that extended mutation analysis is a valuable tool to identify at least some of the missing mutations. Therefore, we suggest extended mutation analysis for the MLC1 gene, if no mutations are found during standard analysis. Hum Mutat 27(6), 505,512, 2006. © 2006 Wiley-Liss, Inc. [source] PHYLOGENY OF THE EUGLENOPHYTES INFERRED FROM SSU AND LSU rDNAJOURNAL OF PHYCOLOGY, Issue 2001Article first published online: 24 SEP 200 Zimmermann, S. & Triemer, R. E. Department of Life Sciences, Rutgers University, Piscataway, NJ 08854 USA The phylogeny of the Euglenophytes has previously been examined using the SSU rDNA. Results from these analyses indicated that the phototrophic genera are not monophyletic. To test this hypothesis, a second gene was sequenced, the LSU rDNA. The taxa used in this study were selected from clades represented in the SSU analyses so that comparisons could be made between gene phylogenies and a combined dataset could be created. Conserved areas of the aligned sequences for both the LSU and SSU were used to generate parsimony, maximum likelihood, and distance trees. Topology of the SSU and LSU trees was similar. The SSU and LSU data consistently generated the same four highly supported terminal clades and varied only in the placement of Euglena stellata and Euglena viridis. The internal nodes of the SSU trees were weakly supported, whereas the LSU provided higher support for these nodes. A combined LSU and SSU dataset was then created. Analysis of the combined dataset yielded trees with identical topologies to those found in the individual datasets and demonstrated strong support for the four terminal clades. These results show that phylogeny of the Euglenophytes as inferred previously from SSU data is confirmed by the LSU data and that the LSU rDNA gene may be useful in elucidating relationships among the major clades. [source] Inheritance of resistance to broomrape (Orobanche cumana Wallr.) race F in a sunflower line derived from wild sunflower speciesPLANT BREEDING, Issue 1 2007L. Velasco Abstract Genetic resistance to broomrape (Orobanche cumana Wallr.) race F in sunflower line J1, derived from the wild perennial species Helianthusgrosseserratus Martens and Helianthus divaricatus L., has been reported to be controlled by dominant alleles at a single locus, Or6. However, deviations from this monogenic inheritance have been observed. The objective of the present study was to gain insight into the inheritance of resistance to broomrape race F in the sunflower line J1. F1, F2, F3 and BC generations from crosses between J1 and three susceptible lines, P21, NR5 and HA821 were evaluated. F1 hybrids showed both resistant (R) and moderately resistant (MR) plants, the latter having a maximum of five broomrape stalks per plant compared with >10 in the susceptible parents. This indicated incomplete dominance of the Or6 alleles. F2 plants were classified as R, MR or susceptible (more than five broomrape stalks per plant). Three different segregation ratios were observed: 3 : 1, 13 : 3 and 15 : 1 (R + MR : S), suggesting the presence of a second gene, Or7, whose expression was influenced by the environment. A digenic model was confirmed, based on the evaluation of F2:3 families. [source] One-plasmid tunable coexpression for mycobacterial protein,protein interaction studiesPROTEIN SCIENCE, Issue 11 2009Yong Chang Abstract A single plasmid that allows controlled coexpression has been developed for use in mycobacteria. The tetracycline inducible promoter, PtetO, was used to provide tetracycline-dependent induction of one gene, while the Psmyc, Pimyc, or Phsp promoters were used to provide three different levels of constitutive expression of a second gene. The functions of these four individual promoters were established using green fluorescent protein (GFP) and a newly identified red fluorescence inducible protein from Geobacillus sterothermophilus strain G1.13 (RFIP) as reporters. The tandem use of GFP and RFIP as reporter genes allowed optimization of the tunable coexpression in Mycobacterium smegmatis; either time at a fixed inducer concentration or changes in inducer concentration could be used to control the protein:protein ratio. This single vector system was used to coexpress the two-protein Mycobacterium tuberculosis stearoyl-CoA ,9 desaturase complex (integral membrane desaturase Rv3229c and NADPH oxidoreductase Rv3230c) in M. smegmatis. The catalytic activity was found to increase in a manner corresponding to increasing the level of Rv3230c relative to a fixed level of Rv3229c. This system, which can yield finely tuned coexpression of the fatty acid desaturase complex in mycobacteria, may be useful for study of other multicomponent complexes. Furthermore, the tunable coexpression strategy used herein should also be applicable in other species with minor modifications. [source] Loss-of-function mutations and inducible RNAi suppression of Arabidopsis LCB2 genes reveal the critical role of sphingolipids in gametophytic and sporophytic cell viabilityTHE PLANT JOURNAL, Issue 2 2008Charles R. Dietrich Summary Serine palmitoyltransferase (SPT) catalyzes the first step in sphingolipid biosynthesis, and downregulation of this enzyme provides a means for exploring sphingolipid function in cells. We have previously demonstrated that Arabidopsis SPT requires LCB1 and LCB2 subunits for activity, as is the case in other eukaryotes. In this study, we show that Arabidopsis has two genes (AtLCB2a and AtLCB2b) that encode functional isoforms of the LCB2 subunit. No alterations in sphingolipid content or growth were observed in T-DNA mutants for either gene, but homozygous double mutants were not recoverable, suggesting that these genes are functionally redundant. Reciprocal crosses conducted with Atlcb2a and Atlcb2b mutants indicated that lethality is associated primarily with the inability to transmit the lcb2 null genotype through the haploid pollen. Consistent with this, approximately 50% of the pollen obtained from plants homozygous for a mutation in one gene and heterozygous for a mutation in the second gene arrested during transition from uni-nucleate microspore to bicellular pollen. Ultrastructural analyses revealed that these pollen grains contained aberrant endomembranes and lacked an intine layer. To examine sphingolipid function in sporophytic cells, Arabidopsis lines were generated that allowed inducible RNAi silencing of AtLCB2b in an Atlcb2a mutant background. Studies conducted with these lines demonstrated that sphingolipids are essential throughout plant development, and that lethality resulting from LCB2 silencing in seedlings could be partially rescued by supplying exogenous long-chain bases. Overall, these studies provide insights into the genetic and biochemical properties of SPT and sphingolipid function in Arabidopsis. [source] Valproic Acid Promotes Neurite Outgrowth in PC12 Cells independent from Regulation of the Survival of Motoneuron ProteinCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2006Jeroen van Bergeijk Spinal muscular atrophy (SMA) is a neurodegenerative disorder of motoneurons. The disease is caused by deletions or mutations of the survival of motoneuron gene 1 (SMN1). The amount of protein expressed from the second gene, SMN2, correlated with the severity of the clinical phenotype. The histone deacetylase inhibitor valproic acid (VPA) has been shown to increase the total cellular amount of functional SMN protein and is therefore considered as a drug candidate for treatment of SMA. In this study, we analyzed the effects of VPA in PC12 cells, a model system for neuronal differentiation, with regard to neurite outgrowth and SMN expression. VPA promoted neurite outgrowth in PC12 cells. However, this effect did not correlate with upregulation of SMN protein levels, suggesting a SMN-independent mechanism for VPA regulation of neurite outgrowth. [source] | ||||||||||